Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Brief Communication
  • Published:

Identification of two novel de novo TUBB variants in cases with brain malformations: case reports and literature review

Journal of Human Genetics volume 66, pages 1193–1197 (2021)Cite this article

Subjects

Abstract

Heterozygous variants in TUBB encoding one of β-tubulin isotypes are known to cause two overlapping developmental brain disorders, complex cortical dysplasia with other brain malformations (CDCBM) and congenital symmetric circumferential skin creases (CSCSC). To date, six cases of CSCSC and eight cases of CDCBM caused by nine heterozygous variants have been reported. Here we report two cases with novel de novo missense TUBB variants (NM_178014.4:c.863A>G, p.(Glu288Gly) and c.869C>T, p.(Thr290Ile)). Case 1 presented brain malformations consistent with tubulinopathies including abnormalities in cortex, basal ganglia, corpus callosum, brain stem, and cerebellum along with other systemic features such as coloboma, facial dysmorphisms, vesicoureteral reflux, hypoplastic kidney, and cutis laxa-like mild skin loosening. Another case presented abnormalities of the corpus callosum, brain stem, and cerebellum along with facial dysmorphisms. We reviewed previous literature and suggest the diversity of clinical findings of TUBB-related disorders.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2

References

  1. Breuss M, Keays DA. Microtubules and neurodevelopmental disease: the movers and the makers. Adv Exp Med Biol. 2014;800:75–96.

    Article  CAS  Google Scholar 

  2. Romaniello R, Arrigoni F, Fry AE, Bassi MT, Rees MI, Borgatti R, et al. Tubulin genes and malformations of cortical development. Eur J Med Genet. 2018;61:744–54.

    Article  Google Scholar 

  3. Breuss M, Heng JI, Poirier K, Tian G, Jaglin XH, Qu Z, et al. Mutations in the β-tubulin gene TUBB5 cause microcephaly with structural brain abnormalities. Cell Rep. 2012;2:1554–62.

    Article  CAS  Google Scholar 

  4. Isrie M, Breuss M, Tian G, Hansen AH, Cristofoli F, Morandell J, et al. Mutations in either TUBB or MAPRE2 cause circumferential skin creases kunze type. Am J Hum Genet. 2015;97:790–800.

    Article  CAS  Google Scholar 

  5. Tadaka S, Hishinuma E, Komaki S, Motoike IN, Kawashima J, Saigusa D, et al. jMorp updates in 2020: large enhancement of multi-omics data resources on the general Japanese population. Nucleic Acids Res. 2021;49:D536–D544.

    Article  CAS  Google Scholar 

  6. Li D, Shen KM, Zackai EH, Bhoj EJ. Clinical variability of TUBB-associated disorders: diagnosis through reanalysis. Am J Med Genet A. 2020;182:3035–39.

    Article  CAS  Google Scholar 

  7. Dentici ML, Terracciano A, Bellacchio E, Capolino R, Novelli A, Digilio MC, et al. Intrafamiliar clinical variability of circumferential skin creases Kunze type caused by a novel heterozygous mutation of N-terminal TUBB gene. Clin Genet. 2018;93:1223–8.

    Article  CAS  Google Scholar 

  8. Boissel S, Fallet-Bianco C, Chitayat D, Kremer V, Nassif C, Rypens F, et al. Genomic study of severe fetal anomalies and discovery of GREB1L mutations in renal agenesis. Genet Med. 2018;20:745–53.

    Article  CAS  Google Scholar 

  9. Wiszniewski W, Gawlinski P, Gambin T, Bekiesinska-Figatowska M, Obersztyn E, Antczak-Marach D, et al. Comprehensive genomic analysis of patients with disorders of cerebral cortical development. Eur J Hum Genet. 2018;26:1121–31.

    Article  CAS  Google Scholar 

  10. Madrigal I, Rabionet R, Alvarez-Mora MI, Sanchez A, Rodríguez-Revenga L, Estivill X, et al. Spectrum of clinical heterogeneity of β-tubulin TUBB5 gene mutations. Gene. 2019;695:12–7.

    Article  CAS  Google Scholar 

  11. Di Donato N, Timms AE, Aldinger KA, Mirzaa GM, Bennett JT, Collins S, et al. Analysis of 17 genes detects mutations in 81% of 811 patients with lissencephaly. Genet Med. 2018;20:1354–64.

    Article  Google Scholar 

  12. Sferra A, Petrini S, Bellacchio E, Nicita F, Scibelli F, Dentici ML, et al. TUBB variants underlying different phenotypes result in altered vesicle trafficking and microtubule dynamics. Int J Mol Sci. 2020;21:1385.

    Article  CAS  Google Scholar 

  13. Basel-Vanagaite L, Sprecher E, Gat A, Merlob P, Albin-Kaplanski A, Konen O, et al. New syndrome of congenital circumferential skin folds associated with multiple congenital anomalies. Pediatr Dermatol. 2012;29:89–95.

    Article  Google Scholar 

  14. Urban Z. The complexity of elastic fiber biogenesis: the paradigm of cutis laxa. J Investig Dermatol. 2012;132:E12–4.

    Article  Google Scholar 

  15. Sanna-Cherchi S, Caridi G, Weng PL, Scolari F, Perfumo F, Gharavi AG, et al. Genetic approaches to human renal agenesis/hypoplasia and dysplasia. Pediatr Nephrol. 2007;22:1675–84.

    Article  Google Scholar 

Download references

Acknowledgements

We would like to thank the patient’s family for participating in this work. This work was supported by Grant‐in‐Aid from the Ministry of Health, Labour and Welfare of Japan, Grants-in-Aid for Scientific Research (B) (JP20H03641) and (C) (JP20K08236) from the Japan Society for the Promotion of Science, the Takeda Science Foundation, and a HUSM Grant-in-Aid from Hamamatsu University School of Medicine. URLs. 8.3KJPN (https://jmorp.megabank.tohoku.ac.jp/202102/downloads/legacy/). gnomAD (http://gnomad.broadinstitute.org/).

Author information

Authors and Affiliations

  1. Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan

    Kazuki Watanabe, Mitsuko Nakashima & Hirotomo Saitsu

  2. Department of Neuropediatrics, Tokyo Metropolitan Neurological Hospital, Tokyo, Japan

    Satoko Kumada & Hideaki Mashimo

  3. Department of Radiology, Tokyo Metropolitan Children’s Medical Center, Tokyo, Japan

    Mikako Enokizono

  4. Department of Pediatric Neurology, Aichi Developmental Disability Center Central Hospital, Kasugai, Japan

    Keitaro Yamada

  5. Department of Pediatrics, Showa University School of Medicine, Tokyo, Japan

    Mitsuhiro Kato

Authors
  1. Kazuki Watanabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mitsuko Nakashima
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Satoko Kumada
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hideaki Mashimo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mikako Enokizono
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Keitaro Yamada
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mitsuhiro Kato
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hirotomo Saitsu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Mitsuko Nakashima or Hirotomo Saitsu.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Watanabe, K., Nakashima, M., Kumada, S. et al. Identification of two novel de novo TUBB variants in cases with brain malformations: case reports and literature review. J Hum Genet 66, 1193–1197 (2021). https://doi.org/10.1038/s10038-021-00956-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s10038-021-00956-4

This article is cited by

Search

Advanced search

Quick links